Opioid analgesics are some of the most commonly prescribed medications in the United States, and are being Increasingly used for chronic pain management. The use of opioids for chronic pain is concerning, given that the drugs are linked to a number of adverse events when used daily, including increased sensitivity to pain (hyperalgesia). Research in both animals and humans suggest that this opioid induced hyperalgesia is mediated via central, neuroplastic changes. Experimental designs have been limited to animal subjects because of their invasive nature, and there is a need to characterize opioid-induced hyperalgesia in humans. New techniques such as real-time functional magnetic resonance imaging (rtfMRI) allow for the experimental, non-invasive modulation of central nervous activity in human participants and therefore present powerful methods for exploring central mechanisms of pain. In the ROO independent research phase of his award. Dr. Younger will conduct a series of studies designed to systematically identify and test central neural mechanisms and substrates of opioid-induced hyperalgesia. The aims will be completed via three projects. Project #1 will extend pilot work carried out in the K99 phase of the award, and will examine the central neural correlates of opioid-induced hyperalgesia in opioid-naTve chronic pain patients. In the longitudinal study, changes in gray and white matter structure, functional response, and functional connectivity between brain regions will be assessed. Those neural changes will then be correlated with behavioral and self-report indicators of opioid-induced hyperalgesia, to determine how brain changes mediate increased pain sensitivity. Project #2 will describe the long-term neural effects of prolonged opioid exposure by examining brain structure and function in opioid-maintained chronic pain patients before and after an opioid detoxification and rehabilitation program. Project #3 will use rtfMRI to experimentally test the role of specific brain structures in the development and maintenance of opioid-induced hyperalgesia. Overarching, secondary goals of all projects are to examine gender differences in the neural response to opioids, and identify individuals who are most at hsk of developing opioid-induced hyperalgesia.